Bis cyclic imides of 3-substituted 2 4 6-triiodoanilines

ABSTRACT

MONO AND BIS CYCLIC IMIDES AND ANILIC ACIDS OF 2,4,6-TRIIODOANILINES BEARING A SUBSTITUTED AMINO GROUP IN THE 3POSITION ARE PREPARED BY DECARBOXYLATION OF THE CORRESPONDING COMPOUNDS BEARING A CARBOXYL GROUP IN THE 5POSITION. THE PRODUCTS ARE USEFUL AS INTERMEDIATES AND AS CHOLECYSTOGAPHIC AGENTS.

United States Patent 3,660,408 BIS CYCLIC IMIDES OF S-SUBSTITUTED2,4,6-TRIIODOAN1LINES James H. Ackerman, Bethlehem, N.Y., assignor toSterling Drug Inc., New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 715,583, Mar.25, 1968. This application July 14, 1969, Ser. No. 841,604

Claims priority, applicatisogsganada, Mar. 18, 1969,

Int. Cl. 607d 31/32 US. Cl. 260-281 2 Claims ABSTRACT OF THE DISCLOSUREMono and his cyclic irnides and anilic acids of 2,4,6-triiodoanilinesbearing a substitutedamino group in the 3- position are prepared'bydecarboxylation of the corresponding compounds bearing a carboxyl groupin the 5- position. The products are useful as intermediates and ascholecystographic agents.

This application is a continuation-in-part of my prior copendingapplication, Ser. No.'7l5,583, filed Mar. 25, 1968, now abandoned.

This invention relates to iodinated aniline derivatives, and moreparticularly is related to cyclic imides and anilic acids of2,4,6-triiodoanilines bearing a substituted amino group in the3-position,,and with intermediates and methods for the preparation ofthese compounds.

A preferred aspect of the invention resides in compounds. of theformulas:

alkyl); R' is hydrogen, lower-alkyl, or hydroxy-loweralkyl; and R" ishydrogenor lower-alkyl.

In the. above Formula A, Y stands for a lower-alkylene 7 group wherein 2or 3 carbon atoms separate the carbonyl groups and thus can be anethylene or propylene group optionally substituted by lower-alkyl. Thegroup Y can have from two to six carbon atoms and includes such groupsas v i and the like. Y also stands for a 2-oxaor 2-thia-1,3- propylenegroup having from 2 to 4 carbon atoms, for example,

and the like. The group Y in Formula B is not limited to a two or threecarbon bridge but represents a single bond or a divalent bridge, ashereinabove defined, having from one to eight carbons separating thecarbonyl and carboxyl groups, optionally interrupted by from one tothree identical members selected from O, S, SO and S0 The terminterrupted means, of course, interposed between carbon atoms and not ina terminal position adjacent to the carbonyl groups.

When R in the above Formulas A and B stands for (lower-alkanoyl)NH,(lower-alkanoyl)NHCH (loweralkanoyl)N(lower-alkyl),(lower-alkoxy-lower-alkanoyl) NH or(lower-alkoxy-lower-alkanoyl)N(lower-alkyl), the lower-alkanoyl grouphas from one to six carbon atoms thus including, for example, formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, caproyl, and the like.

When R stands for (lower-alkanoyl)N(lower-alkyl),(lower-alkoxy-lower-alkanoyl)N(lower-alkyl), or

and/or R stands for lower-alkyl, and/or R" stands for lower-alkyl, thelower-alkyl group has from one to four carbon atoms, thus including, forexample, methyl, ethyl, propyl, isopropyl, and butyl.

.When R stands for (lower-alkoxy-lower-alkanoyl)NH or (lower alkoxylower alkanoyl)N(lower-alkyl), the lower-alkoxy groups have from one tofour carbon atoms and thus include, for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, and the like.

The compounds of the invention of Formulas A and B above are prepared bydecarboxylation of compounds of Formulas C and D, respectively, asfollows: (300E (300R 1 IWI c0 I hr -N Y R@ \g()/ R--- N---COYOO0R" I I Rwherein Y, Y, R, R and R" have the same meanings given hereinabove. Thedecarboxylation is carried out by heating a compound of Formula C or D,either in the free acid or salt form, in an organic solvent. A preferredmethod is heating the free acid or salt form, for example, the sodiumsalt, in dirnethylformamide at a temperature between about and C.

. The intermediate carboxylic acids of Formulas C and .D are the subjectof my copending application, Ser. No.

808,653, filed Mar. 19, 1969, a continuation-in-part of abandonedapplications Ser. Nos. 550,614 and 715,558, filed May 17, 1966 and Mar.25, 1968, respectively, and

' are prepared as described below.

7 The method of preparation of the compounds of Formulas C and D variesaccording to the structure desired as follows:

(1) Compounds of Formula C where R is (loweralkanoyl)NHCH (loweralkanoyl)N(lower alkyl), (lower-alkoxy-lower-alkanoyl) N (lower-alkyl)co Y/ \N 6 or HOOCYCON(lower-alkyl) (a) Using a dibasic acidanhydride.-A compound of the formula COOH R NHQ (E) wherein R has themeaning given above under (1), and Q is hydrogen or lower-alkanoyl, isheated with an acid anhydride of the formula When Y is a lower-alkylenegroup, the reaction is pref- (a) Where Y is within the scope of Y, and Ris hydrogen.-These compounds can be prepared by alkaline hydrolysis ofthe corresponding compounds of Formula C. The reaction takes place inaqueous solution under mild conditions, at room temperature. Under theseconditions the amide linkage to the 3-amino group is unaffected.

(b) Where R is as given under method 1 above.- These compounds can beprepared by reacting a compound of Formula E where Q is hydrogen with ahalf ester half acid chloride, ClCO-Y'COOR, in an inert solvent,affording a compound of Formula D where R? is lower-alkyl. Hydrolysis ofthe latter under mild alkaline conditions gives an anilic acid ofFormula D where R" is hydrogen.

15 (3) Compounds of Formulas C and D wherein R is (lower-alkanoyl)NH or(lower-alkoxy-lower-alkanoyl) NH These compounds can be prepared from3-amino-5- erably carried out in the presence of a strong acid cat- 20nitrobenzoic acid according to the following flow sheet:

COOK

COOK

COOH

COOK

(c, a a H s) (lower-alkanoyDNH- Alkanoie Anhydride COOK COOH

n w NHCO-Y-COOH n w NHCO-Y-QOOH (n, R 14 M, n' and a" a) AlkanoioAnhydride COOK Y (lower -a lkanoyl) 3-amino-5-nitrobenzoic acid isreacted with an anhydride, O(CO) Y, to give the cyclic imide (F). Thelatter- 1 can either be hydrogenated under acid or neutral conditions togive the amino cyclic imide (G) or hydrolyzed under basic conditions togive the corresponding nitroanilic acid (H). The nitro-anilic acid inturn can be hydrogenated to the amino-anilic acid (J). Iodination of theamino cyclic imide (G) affords a compound of Formula C wherein R is H N,and iodination of the amino- 75 anilic acid (J) gives a cornpound ofFormula D where R is H 1 1 and R is H. The primary-amino groups canthen, if desired, be acylated with a lower-alkanoic acid anhydride orlower-alkoxy-lower-alkanoic acid anhydride to give, respectively, acompound of Formula C- where R is (lower-alkanoyDNH or(lower-alkoxy-lowerealkanoyl)NH, or a compound of FormulaD where R is(lower-alkanoyl)NH or (lower-alkoxy-lower-alkoxy)NH and R is hydrogen. i

(4) Compounds of Formulas C and D where the groups in ,the 3- and5-positions are identical These are most conveniently prepared from3,5-diamino-2,4, 6-triiodobenzoic acid. The latter is reacted with atleast two equivalents of an hydride, O(CO) Y, to afford a compound ofFormula Cwhere R is Y(CO) N, which then can be hydrolyzed to a compoundof Formula D where is HOOCY-CONH and R and R" are H. The startingmaterial can also consist of a3-loweralkanoylamino-S-amino-Z,4,-6-triiodobenzoic acid or a 3,5-bis(lower-alkanoylamino)benzoic acid. In the reaction with the anhydridethe lower-alkanoyl groups are replaced by cyclic imide groups.Alternatively, a method analogous to method 2(b) above can be used,i.e., reacting 3,5-diamino-2,4,6-triiodobenzoic acid with a half esterhalf acid chloride ClCOY'-CO- OR", affording a compound of Formula Bwhere R is' R0COY--CONH, R is H and R" is loWer-alkyl.

(5.) Compounds of Formula D wherein R is lower-alkyl orhydroxy-lower-alkyl These compounds canbe prepared by N-alkylation ofthe corresponding compounds where R is hydrogen. The alkylation iseffected by'the action of a lower-alkyl or hydroxy-loWer-alkyl halide,sulfate, alkylsulfonate or arylsulfonate in the presence of aqueousalkali. If the starting material is a compound of Formula D where R is(lower-alkanoyl .NH or HOOCY'-CONH, alkylation occurs on both nitrogenssimultaneously.

The compounds of the invention where Y and/or Y are alkylene groupsinterrupted by S0 or S0 can alternatively be prepared by oxidation ofthe corresponding sulfide (--S) compounds with a peracid or hydrogenperoxide. The reaction takes place at room temperature in an inertorganic solvent.

. Alternatively, the compounds of Formulas A and B can be prepared fromcompounds of the formula:

wherein R" is H N, (lower-alkanoyDNH, (lower-alkanoyl)NHC H(lower-allranoyl)N(lower-alky1), (loweralkoxy-lower-alkanoylN(lower-alkyl) or HOOC--YCO-'--N(lower-alkyl), where Y has the meaninggiven hereinabove, and Q is hydrogen or loweralkanoyl by formation ofthe cyclic imides and anilic acids by methods analogous to thosedescribed above for the preparation of compounds of Formulas C and D.The compounds of Formula K are in turn prepared by decarboxylation ofthe compounds of Formula -E or by other procedures known in the art asillustrated by the specific examples hereinbelow.

The structures of the compounds of the invention were determined by themodes of synthesis, by elementary analysis and by neutralequivalent.determinations. The course of the reactions was followed by thin-layerchromatography.

Those compounds of the invention which are carboxylic acids can beobtained in the form of salts derived from inorganic bases or organicamines. Preferred salts are those which are pharmaceutically acceptable,for example, the sodium magnesium, calcium and N-methylglucamine salts;although all salts are useful either as characterizing derivatives oras'intermediates in the purification of the 2101 s.

The compounds of the invention having the Formula A wherein R is and thecompounds of the invention having the Formula B are useful as X-raycontrast media for visualization of the gallbladder (cholecystography).The compounds have intravenous toxicity (approximate LD values) in therange between 600 and 7500 mg./lcg. in mice. The compounds of lessertoxicity, LD =1500 mg./ kg. or greater, are primarily useful, in theform of their water-soluble, pharmaceutically acceptable salts, asintravenous cholecystographic agents. The compounds having LD valuesless than about 1500 mg./kg. are primarily useful, either in the freeacid or salt form, as oral cholecystographic agents. 7

The actual quantitative determination of toxicity and radiopaqueeffectiveness for a particular compound is readily determined bystandard test procedures by technicians trained in pharmacological testprocedures, without the need for any extensive experimentation.

The compounds were tested for their intravenous cholecystographiceflicacy by standard procedure as follows: The test compound wasinjected intravenously in the form of an aqueous solution of the sodiumor N-methylglucamine salt to cats. Each cat was X-rayed at selected timeintervals and the roentgenograms examined and evaluated. The density ofthe gall-bladder shadows was interpreted in accordance with a numericalscoring plan designated as the Cholecystographic Index (CI), a measureof the efiiciency of the test compound, viz: 0 (none), 1 (poor), 2(fair), 3 (good), 4 (excellent) [see J. O. Hoppe, J. Am. Pharm. Assoc.,Sci. Ed. 48, 368-79 (1959)].

In testing for oral cholecystography, the test compound was administeredorally in capsules to each of five cats. About eighteen hours later,each cat was X-rayed and the roentgenograms were examined. The densityof the gallbladder shadow evoked by the test compound in each cat wasinterpreted in accordance with the above numerical scoring plan and theAverage Cholecystographic Index (ACI) determined.

The compounds of the invention, upon testing for cholecystographiceffectiveness in cats at a dose of mg./kg., were found to producegallbladder shadows having a Cholecystographic Index of 3.0-4.0 eitherby oral or by intravenous administration.

The compounds of the invention are prepared for choleeystographic use bydissolving a pharmaceutically acceptable salt from in sterile aqueousmedium suitable for intravenous injection; or incapsule or in tabletform with conventional excipients for oral administration.

The compounds of Formula A, wherein R is (loweralkanoyDNH,(lower-alkanoyDNHCH (lower-alkanoyl)N(loWer-alkyl),lower-alkoyy-lower-alkanoyl)NH,(lower-alkoxy-lower-allranoyl)N(loweralkyl) or are useful asintermediates, by hydrolytic cleavage, for the preparation of compoundsof Formula B.

The following examples will further illustrate the invention.

, 7 EXAMPLEI (a) 3,5 bis(Glutarimido)-2,4,6-triiodobenzoic Acid [C; R is"-(CH (CO) N-,"Y" is CH CH CH was-prepared from 265" of3,5-diarnino-2,4,6-triiodobenzoic acid, 400 g. of-g'lutaric anhydrideand 18ml. of concentrated sulfuric. acid, heated and stirred forseventeen hours. The product was recrystallized from dimethyl sulfoxide,adding water toinduce precipitation, and was obtained as a light graysolid with one mole of dimethyl sulfoxide of crystallization, M.P. above300 C. A. sample of the acid was converted to its sodium form, M.P. 288-291 C. (dec.) when recrystallized from water.

(b) N,N' (2,4,6-triiodo-m-phenylene)diglutarimide [A; is R is (CH (CO)N, Y is CH CH CH ].-'A mixture of 89.10 g. of sodium3,5-bis(glutarimido)-2,4,6-triiodobenzoate and 400 ml. ofdimethylformamide was warmed at 85 C. for 20 minutes to effect solution,and then heated at reflux temperature (130-135 C.) for four hours. Thesolution was cooled, and the solid product collected, washed withdimethylformamide and acetone, and dried to constant weight (35.18 g.).An additional 41.75 g. of product was obtained by diluting the filtratewith water. The combined product was recrystallized from acetic acid,using activated charcoal for decolorizing purposes, to giveN,N'-(2,4,6-triiodo-m-phenylene)diglutarimide, colorless prisms, M.P.above 300 C.

N,N'-(2,4,6-triiodo-m-phenylene)diglutarimide can also be prepared byreacting 3-amino-2,4,6-triiodoaniline (K; R is H N, Q is H),3-amino-2,4,6-triiodoacetanilide (K; R is H N, Q is COCH orS-acetamido-2,4,6-triiodoacetanilide (K; R is CH CONH, Q is COCH withglutaric anhydride according to the procedure of Example 1, part (a).

EXAMPLE 2 (a) 3 glutarimide (N-methylacetamido)-2,4,6- triiodobenzoicand [C; R is CH CON(CH Y is CH CH CH ].A mixture of 117.2 g. of3-amino-5-(N- methylaceta'rnido)-2,4,6-triiodobenzoic acid and 182 g. ofglutaric anhydride was heated with stirring on a steam bath.Concentrated sulfuric acid ml.) was added, and heating and stirring werecontinued for seven hours. The reaction mixture was added to 700 ml. ofwater, and the solid product was collected by filtration andrecrystallized from acetic acid. The resulting 3 glutarirnido-S-(N-methylacetamido)-2,4,6-triiodobenzoic acid was converted to its sodiumsalt form as follows: the free acid was slurried with 40 ml. of methanoland a 1 N solution of sodium hydroxide in methanol was added withtrituration until the solid had dissolved. The sodium salt wasprecipitated out with ether, and the resulting gum was triturated withether and dissolved in methanol. The latter solution was decolorizedwith activated charcoal and the product reprecipitated with ether. Theproduct was dissolved in water and the solution filtered andconcentrated in vacuo. The residue was dried in vacuo to give the sodiumsalt of 3-glutarimido-5-(N-methylacetamido)- 2,4,6-triiodobenzoic acidas a pale pink solid, M.P. 200- 204 C. (dec.).

(b) N [2,4,6-triiodo-3-(N-methylacetamido)phenyl]- glutarimide [A; R isCH CON(CH3), Y is CH CH CH can be prepared by decarboxylation of sodium3-glutarimido 5-(N-methylacetamido)-2,4,6-triiodobenzoate according tothe procedure of Example 1(b); or by decarboxylation of3-acet-amido-5-(N-methylacetamido)-2,4,6- triiodobenzoic acid followedby reacting the resulting 3- (N-methylacetamido)2,4,6-triiodoacetanilide [K; R is CH CON(CH Q is COCH with glutaricanhydride.

By replacing the 3 amino-5-(N-methylacetamido)- 2,4,6-triiodobenzoicacid in the foregoing preparation by a molar equivalent amount of3-amino-5 (N -butylacetamido -2,4,6-triiodobenzoic acid,3-amino-5-(N-methylpropionamido)-2,4,6-triiodobenzoic acid,

'benzloic'acid, My Ev 3-amino-5-(N,N=dirnethylcarbamoyl) 2,4,6 triiodo l'3-amino-5-(N-nre'thylcaproylarnind)-2,4,6-triiodo benzoic acid,'or v v3-amino-5- (N-methyl 2 methoxyacetamido -2,4,6-tri- 10dObfiZ6iQ Qacid,there can be obtained, respectively,

3-glutarimido-5-(N-butylacetamido)-2,4,6-triiodobenzoic acid [C; R is OHCON(C H Y is cn crr cn v v3-glutarimido-5-(N-methylpropionamido)-2,4,6-triiodobenzoic acid [C; Ris CH CH CON(OH Y is 2 2 2],

3-glutarimido-5-(N-rnethylcaproylamino)-2,4,6-triiodobenzoic acid [C; Ris CH (CH CON(CHZ), Y'is CH CH CH v 43-glutarimido-5-(N,'N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid [C; Ris (CH NCO, Y is CH CH CH 3-glutarimido-5-(N-methyl-Z-methoxyacetamido)-2,4,6- triiodobenzoic acid [C; R is CH OCHCON(CH Y is I p EXAMPLE 3 (a) 3-succinimido-5-(N-rnethylacetamido)2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y, is CH CH was preparedfrom 87.9 g. 3 amino 5 (N-methylacetamido)-2,4,6-triiodobenzoic,acid, g.of succinic anhydride and 6 ml. of sulfuric acid according to theprocedure of Example 2, except that a reaction temperature of C. wasused. The reaction was essentially complete after 30 minutes heatingtime. The compound was isolated in the form of its sodiumsalt, paleyellow solid, M.P. 220-222 C. (dec.).

(b) N-[2,4,6-triiodo-3 (N-methylacetamido)phenyl] succinimide [A; R isCH CON(CH ),-Y is CH CH ]-can be prepared by heating sodium3-succinimido-5-(N-methylacetamido)-2,4,6-triiodobenzoate indimethylt'ormamide by the method described in Example 1( b).

EXAMPLE 4 (a) 3 (3-methylglutarirnido) 5(methylacetamido)-2,4,6-triiodobenzoic acid [C;R is CH5CON(CH Y is CHCH(CH )CH was prepared-from 3-ari1in0-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 3-r'nethylglutaricanhydride and sulfuric acid according'to the procedure of Example 2. Theproduct-was isolated 'in the'free acid form, M.P. 301-302 C. (decL) whenrecrystallized from acetic acid. I a

(b) N- 2,4,6-triiodo-3- (N-methylacctamido)phenyl -3- methylglutarirnide[A; R is CH CON(CH Y is can be prepared by heating sodium3-succiniinido-5-(N- inethylamido)-2,4,6-triiodobenzoate indimethylformam ide by the method described in Example 1(b).

9 following compounds were prepared following the procedureof Example 1from the appropirate 3-amino- R 2,4,6-triiodobenzoic acid and acidanhydride:

EXAMPLE 5 EXAMPLE 6 j 3-glutarimido-5-(N-ethylacetamido)2,4,6-triiodoben- ZOiC acid [C;' R is CH C-ON(C H Y is CH CH CH Sodiumsalt form, MJP. above 220 C.

EXAMPLE 7 3-(methylsuccinimido) 5 (N-methylacetamido)-2,4,G-triiodobenzoic acid [C; R is CH CON(CH Y is CH(CH )CH CH2], M.P.285287 C. (from acetic acid); sodium salt form, M.P. above 245 C.(dec.).

EXAMPLE 8 EXAMPLE 9 3 (3,5-dioxothiomorpholino)-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid R is CH CON(CH Y is CH SCH sodium salt form,beige solid, M.P. 250-260 C. (dec.).No sulfuric acid wasused in thispreparation.

The compounds of Examples 5, 6 and 7 can be decarboxylated by the methodof Example 1(b) to produce, respectively, N-[2,4,6-triiodo 3(N-methylacetamido)- phenyl] -3,3-dimethylglutarimide [A; R is CH CON(CH Y is CH C(CH CHN-[2,4,6'-triiodo-3-(N-ethylacetamido)phenyl]glntarimide [A; R is CHCON(C2H5), Y is CHgCI-I CH andN-(2,4,6-triiodo-3-(N-methylacetamido)phenyl]methylsuccinimide [A; R isCH CON(CH Y is CI -I(CH )CH CH The compounds of Examples 8 and 9 Weredecarboxylated by heating the free acid forms in dimethylformamide, 90'minutes at reflux temperature. There was obtained, respectively,N-[2,4,6-triiodo 3 (N-methylacetamido) phenyl]diglycolimide [A; R is CHCON(CH Y is CH OCHZ], M.P. 264-266" C. (from dimethylformamide); and 4-[2,4,6-triiodo-3-(N-methylacetamido)phenyl]- '3',5-thiamorpholinedione[A; R is CH CON(CH Y is CH SCH beige solid, M.P. 283285 C. (from aceticacid). The latter two compounds were also prepared by heating togetherat 120-150 C. equal weights of 2,4,6- triiodo3-(N-methylacetamido)aniline and diglycolic anhydride or thiodiaceticanhydride, respectively.

3(3,5 dioxothiomorpholino) (N-methylacetamido)-2,4,6-triiodobenzoic acidcan be oxidized with m-chloroperbenzoic acid in dimethylformamidesolution to give 3 -(3,5,S,s tetraoxothiomorpholino) 5(N-methylacetamido)-2,4,6-ti'iiodobenzoic acid [C; R is CH CON(CH Y isCH SO CH which can be decarboxylated according to the procedure ofExample 1(b) to give4[2,4,6-triiodo-3-(N-methylacetamido)phenyl]-3,5,'SStetra'oxothiomorpholine [A; R is CH CON(CH Y is CH SO CH EXAMPLE l0 (a)3' carboxy-5-(N-methylacetamido)-2',4',6-triiodogluta ranilic acid [D; Ris CH CON(CH R and R" are H, Y is CH CH CH ].A mixture of 58.6 g. of 3-amino-S-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 74 g. of glutaricanhydride and 8 ml. of concentrated sulfuric acid was heated on a steambath for five hours. The reaction mixture was poured into water and thesolid product collected by filtration; The product, consisting of3-glutarimido-5-(N-methylacetamido) 2,4,6 triiodobenzoic acid (Example2) was dissolved in excess dilute aqueous sodium hydroxide, and thesolution warmed for thirty minutes, then cooled and 3 N hydrochloricacid added slowly until precipitation was complete. The solid productwas collected and recrystallized first from acetone, then from aceticacid, and finally from water to give 3'- carboxy 5'-(N-methylacetamido)2,4',6'-triiod0glutaranilic acid, colorless prisms, M.P. 188.8196 C.

(b) 2',4,6'-triiodo-3 N-methylacetamido) glutaranilic acid [B; R is CHCON(CH3), R and R are H, Y is CH CH CH can be prepared by heating thedisodium salt form of 3'-carboxy-5'-(N-methylacetamido)-2,4',6'-triiodoglutaranilic acid in dirnethylformamide according to theprocedure of Example 1(b).

EXAMPLE 11 (a)3-carboxy-5'-(N-methylacetamido)-2,4',6-triiodosuccinanilic acid [D; Ris CH CON(CH R and R" are H, Y is CH CH was prepared from 34.3 g. of3-amino- S-(N-rnethylacetamido)-2,4,6-triiodobenzoic acid, 82 g. ofsuccinic anhydride and 5 ml. of concentrated sulfuric acid, followed byalkaline hydrolysis of the resulting 3-succinimido-5-(N-methylacetamido)2,4,6 triiodobenzoic acid, according to the method described in Example10. The product was recrystallized from dilute ethanol and from amethanolacetonitrile mixture and further purified by converting it tothe diammonium salt by means of ammonium hydroxide in methanol, and thenacidifying an aqueous solution of the ammonium salt to regenerate thefree acid. There was thus obtained 3-carboxy-5-(N-methylacetamido)-2',4,6'-triiodosuccinanilic acid, M.P. 275.()276.0 C.(dec.).

(b) 2,4',6-triiodo-3'-(N-methylacetamido)succinanilic acid [B; R is CHCON(CH R and R" are H, Y is CH CH colorless prisms, M.P. 209-211 C., wasprepared from 37.81 g. of disodium 3-carboxy-5-(N-methylacetamido)-2,4,6'-triiodosuccinanilate in ml. ofdimethylformamide, 40 minutes at reflux. The mixture was acidified withhydrochloric acid and the product collected and recrystallized fromacetone.

Similarly, by warming in dilute aqueous sodium h vdroxide,

3-glutarimido-5- (N-butylacetamido -2,4,6-triiodobenzoic acid,

3-glut arimido-S- N-methylpropionamido) -2,4,6-triiodobenzoic acid,

3-glutarimido-5-(N-methylcaproylamino)-2,4,6-triiodobenzoic acid, or

3-glutarimido-5-(N-methyl-2-methoxyacetamido)-2,4,6-

triiodobenzoic acid can be hydrolyzed, respectively, to

3' carboxy-5-(N-butylacetamido)-2,4,6'-triiodoglutaranilic acid [D; R isCH CON(C H R and R are H, Y is CH CH CH 3'carboxy-5-(N-methylpropionamido)-2',4,6-triiodoglutaranilic acid [D; Ris CH CH CON(CH R and R are H, Y is CH CH CH 3-carboxy 5'(N-methylcaproylamino)-2',4',6'-triiodoglutaranilic acid [D; R is CH (CHCON(CH R and R are H, Y is CH CH CH 0r 3-carboxy 5'(N-methyl-2-methoxyacetamido)-2',4,6'r triiodoglutaranilic acid [D; R isCH OCH CON(CH R and R" are H, Y is CH CH CH and in turn decarboxylatedto give, respectively,

3'-(N-butylacetamido)-2',4',6'-triiodoglutaranilic acid [B;

R is CH CON(C H R and R" are H, Y is CH CH CH 3'- (N-methylpropionamido-2',4',6'-triiodoglutaranilic acid [B; R is CH CH CON(CH3), R and R areH, Y is CH CH CH 3-(N-methylcaproylamino) 2,4',6' triiodoglutaranilicacid [B; R is CH (CH CON(CH R and R are H, Y is CH CH CH or ClCOCH CH CHCH COOCH ClCOCH CH OCH CH COOCH Cl-COCH CH OCH CH OCH CH OCH CH COOCH Orto give, respectively, the following compounds: [D; R is CH CON (CH R,is H, R" is CH3, Y is R is CH CON(CH R is H, R" is CH Y is CH CH OCH CH[D; R is CH CON(CH R is H, R is CH Y is CH CH OCH CH OCH CH OCH CH or[D; R is CH CON(CH R is H, R is CH Y is CH SCH CH CH CH SCH These can behydrolyzed to the corresponding dibasic acids where R is hydrogen anddecarboxylated to give, respectively, the following compounds: [B; R isCH CON(CH R and R are H, Y is CH CH CH CH [B; R is CH CON(CH R and R"are H, Y is CH CH OCH CH [B; R is CH CON(CH R and R are H, Y is CH CHOCH CH OCH CH OCH CH or [B; R is CH CON(CH R and R are H, Y is CH SCH CHCH CH SCH The starting half-ester half-acid chlorides are a known classof compounds readily prepared by partial hydrolysis of the correspondingdi-esters followed by reaction of the resuting half-esters with thionylchloride.

In the same manner, 3,5-diamino-2,4,6-triiodobenzoic acid can be causedto react with Cl--CCH CH CH CH COOCH to give [D; R is CH OCOCH CH CH CHCONH, R is H, R is CH Y is CH CH CH CH which can be hydrolyzed to give[D; R is HOCOCH CH CH CH CONH, R and R" are H, Y is CH CH CH CH and thelatter decarboxylated to give [B R is HOCOCH CH CH CH CONH R and R areH, Y is CH CH CH CH EXAMPLE 12 (a) 3 [2(carboxymethylsulfonyl)acetamido]-2,4,6-triiodo-S-(N-methylacetamido)benzoic acid [D; R is CH CON(CH R' and Rare H, Y is CH SO CH ].A solution of 26.1

g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic H acid in 300ml. of dioxane was distilled until about 60 ml. of dioxane was removedin order to eliminate possible traces of water. Sulfonyldiacetylchloride CICOCH SO CH COCl) (5.85 'g.) was then-added, and the mixturewa's stirred and refluxed forabout five days. The reaction mixturew'asconcentrated in vacuo to remove the solvent,' and" tlie residue wasdissolved in dilute sodim hydroxide to give a solution of the sodiumsalt of the product. The basic solution was made weakly acid, which didnot causeprecipitation of the acid form of the product, treated-withactivated charcoal at C. and filtered. The filtrate yf/a's acidifiedwith 3 N hydrochloric acid and the precipitated product collected. Theacid product was purified by'dissolving it in ammonium hydroxidesolution and reacidifying the resulting ammonium salt solution. Theacidprodnot was recrystallized from aqueous dimethylformamide to give3-[2 (carboxymethylsulfonyl)acetamid0];2,4,6-triiodo-S-(N-methylacetamido)benzoic acid, M.P. above 300 C.

(b) {N-[2,4,6 triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylsulfonyl}acetic acid [B; R is w A CH CON(CH R and R" areH, Y is CH SO CH can be prepared by decarboxylation of 3-[2(carboxymethylsulfonyl)acetamido]-2,4,6triiodo-S-(N-methylacetamido)benzoic acid according to the procedure ofExample 1(b). The product is the same as that described in Example 20below. L

By replacing the sulfonyldiacetyl chloride in-thefore going preparationby sulfoxydiacetyl chloride there can be obtained3-[2-(carboxymethylsulfoxy)acct: amido -2,4,6-triiodo-5-N-methylacetamido) benzoic acid [D; R is CH CON(CH R and R are H, Y isCH SOCH which can be decarboxylated to give {N-[2,4,6-triiodo-3.- (Nmethylacetamido)phenyl]carbamoylmethylsulfoxy} acid [B; R is CH CON(CH Rand R ar e H, Y is CH2SOCH21- 1 v i-'- ":3;

The following compounds can be prepared eitherlby mild alkalinehydrolysis of the corresponding cyclic imides, or directly from theappropriate 3-amir1o=5-R-2,4,6-triiodobenzoic acid without isolation ofthe intermediate cyclic imide, followed by decarboxylation of theresulting anilic acid, as described above inExamples wand 11.

EXAMPLE 13' (a) 3-carboxy-2,4,6-triiodo-3-methyl -,-5 (N-meth-zylacetamido)glutaranilic acid [D; R is CH CON(CH R and R are H, Y is CHCH(CH CH ],.colorless crystals, M.P. 256259 C. (dec.). v i

(b) 2,4',6' triiodo-3-methyl-3-(N-methylacetamido)- glutaranilic acid[B; R is CH CON(CH R'- and R".are' H, Y is CH CH(CH )CH pale tancrystals fromaque: ous acetic acid, M.P. 189-193 C.; sodium salt =form,beige powder from methanol-ether, M.P. 202-204 Cu EXAMPLE 14 (a) 3carboxy 2,4,6-triiodo-3,3-dimethyl-5-(H methylacetamido)glutaranilicacid [D; R is 1 I CH3CON(CH3) R and R are H, Y is CH C(CH CH colorlesscrystals, M.P. 258262" C. (dec.).

13 (b) 2',4',6' triiodo 3,3 dimethyl 3'-(N-methylacetamido)glutaranilicacid [B; R is CH CON(CH R' and R" are H, Y is 'CH C(CH CH tan powder,M.P. 132 134 C. v p EXAMPLE 16 (a) 3' carboxy 2', 4', 6'-triiodo-3-methyl-5-(N- methylacetamido)succinanilic acid '[D; R is Rand R" are I-L-Y' is CH(CH )CH light orange Slid,-I\l.P. 262 -2 64 C.(dec.)J

(b) 2',4,6' triiodo-3-methyl{3"-(N-methylacetamido) succinanilic acid[B; R is CHCON(CH3), R and R are H, Y is cruougcu EXAMPLE 18 (a) 3carboxy 2,4',6' triiodo--(N-methylacetamido)diglycolanilic acid [D; R isCH C-ON(CHa), R and R" are H, Y is CH OCH disodium salt form, light tansolid, M.P..245260 .C. (dec.).

(b) 2,4',6 I- triiodo-3 (N m'ethylacetamido)diglycolanilic acid [B; R isCH CON(CH R and R" are H, Y' is CH OCH colorless S'Olid,M.P. 125-133 C.

2 EXAMPLE 19.

(a) 3 [2 (carboxymethylthio)acetamido] 2,4,6-triido-S-(N-methylacetamido)benzoic acid [D; R, is CH CON(CH3), R'and R"are H, Y is CH SCH beige solid,'-M.P. 16517,0..C.

(b) {N [2,4,6 triiodo 3-(N methylacetamido) phenyl]carbamoylmethylthio}aceticacid [B; R is CH3CON(CH3) R- and R" are H, Yis or-r scrr EXAMPLE 20 {N [2,4,6 triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylsulfonyl}acetic acid [B; R is CH CQN (CH R 1 and R" areH, Y is CH SO CH ].{N- [2,4,6 triiodo' 3 "(N methylacetamido)phenyl]carbamoylmethylthio}acetic acid (derived by hydrolysis of 25.0 g. .of4-[2,4,6-triiodo-3 (N-methylacetamido) phenyl]e3,'5thiamorpholinedione)was dissolved in 150 ml'. 'of glacial acetic acid at 40 C. Hydrogenperioxide (72 ml. 30%) was added. After five minutes the mixture wasconcentrated to a volume of 75 ml. and 400 ml. of water added.Theprodu'ct which separated was crystallized by stirring the mixture inice, and was collected and dried to give{N-[2,4,6-triiodo-3-(N-methylacetamido)phenyl]carbamoylsulfonyl}aceticacid, M.P. 148- 150" (dec.).

' EXAMPLE 21 (a) 3 -"succinimido 5 nitrobenzoic acid [F; Y is CH CH wasprepared by heating 3-amino-5-nitrobenzoic acid with succinic anhydridein the presence of sulfuric acid. It had the M.P. 262-268 C. whenrecrystallized from aqueous dimethylformamide.

(b) carboxy 5 nitrosuccinanilic acid [H; Y is CH CH vwas prepared bytreating 3-succinimido-5-nitrobenzoic acid with warm dilute aqueoussodium hydroxide, and had the M.P. 220221 C.

i '(c) 3' cal-boxy 5f -'aminosuccinanilic acid [1; Y is CH CH 3' carboxy--5'-nitrosuccinanilic acid (83.5 g.) and 50 ml. of concentratedammonium hydroxide in ml. of water were added to a heated solution of540 g. of ferrous sulfate heptahydrate in 900 ml. of water. Concentratedammonium hydroxide (100 ml.) was then added during fifteen minutes in 50ml. portions. After thirty minutes of heating on a steam bath, thereaction mixture was filtered and made acid to pH 3.5. The product wascollected and dried in vacuo over phosphorus pentoxide to give 57.5 g.of 3'-carboxy-5'-aminosuccinanilic acid, M.P. 194 C. (dec.).

(d) 3' carboxy 5 amino-2',4',6'-t1iiodosuccinanilic acid [D; R is NH R'and R" are H, Y is CH CH ].Potassium iododichloride (335 ml. 2.23 N inwater), was added over a period of forty minutes to a stirred suspensionof 57.3 g. of 3'-carboxy-5-aminosuccinanilic acid in 435 ml. of water.The solid product was. collected by filtration and recrystallized fromwater and from aqueous dimethylformamide. The product was purified byconverting it to the diammonium salt and then to the disodium salt, M.P.222-225 C. (dec.). The latter was acidified to product the free acidform of 3'-carboxy- 5'-amino-2,4',6-triiodosuccinanilic acid, creamcolored solid, M.P. 156.2-172.2 C. (dec.).

3' carboxy 5' amino 2',4',6'-triiodosuccinanilic acid can be acylatedwith acetic anhydride, using a few drops of perchloric acid as acatalyst to obtain 3-carboxy- 5' acetamido 2',4,6'-triiodosucciuanilicacid [D; R is CH CONH, R and R" are H, Y is CH CH which can bedecarboxylated according to the method of Example 1(b) to give2',4',6-triiodo-3-acetamidosuccinanilic acid [B; R is CH CONH, R and R"are H, Y is CH CH EXAMPLE 22 (a) 3 glutarimido 5 nitrobenzoic acid [F; Yis CH CH CH was prepared by heating a mixture of 18.2 g. of3-amino-5-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml.of concentrated sulfuric acid on a steam bath for two hours. The productwas isolated and recrystallized from aqueous dimethylformamide to give3- glutarimido-S-nitrobenzoic acid, pale yellow prisms, M.P. above 300C.

(b) 3 glutarimido 5 aminobenzoic acid [-G; Y is CH CH CH can be preparedby reduction of 3-glutarimido-5-nitrobenzoic acid. The reduction can becarried out catalytically (platinum or nickel catalyst) under neutral oracidic conditions.

(0) 3 glutarimido 5 amino-2,4,6-triiodobenzoic acid [C; R is H N, Y isCH CH CH can be prepared by iodination of 3-glutarimido-5-aminobenzoicacid with potassium iododichloride according to the procedure describedin Example 21, part (d).

(d) 3 glutarimido 5-acetamido-2,4,6-triiodobenzoic acid [C; R is CHCONH, Y is CH CH CH can be prepared by acetylation of3-g1utarimido-5-amino-2,4,6-triiodobenzoic acid with acetic anhydride,using a few drops of perchloric acid as a catalyst.

(e) 2,4',6 triiodo 3-acetamidoglutaranilic acid [B; R is CH CONH, R andR" are H, Y is can be prepared by hydrolysis and decarboxylation of 3-glutarimido-5-acetamido-2,4,6-triiodobenzoic acid. Alternatively, 3glutarimido 5 amino 2,4,6-triiodobenzoic acid can be converted by mildhydrolysis to 3-amino-5'-. carboxy-2',4',6-triiodog1utaranilic acid, thelatter decarboxylated to give 3-amino-2',4',6'-triiodoglutaranilic acid,M.P. 225-228" C., which is then acetylated to give2',4',6'-triiodo-3'-acetamidoglutaranilic acid.

EXAMPLE 23 (a) 3'-carb0xy-5 amino-2',4',6'-triiodo-N methylglutaranilicacid [D; R is H N, R is CH R" is H, Y is CH CH CH ].-To a solution of26.0 g. of 3'-carboxy- 5-amino-2',4,6'-triiodoglutaranilic acid[prepared by hydrolysis of 3-g1utarimido-5 amino 2,4,6-triiodobenzoicacid (Example 22c)] in 100 ml. of 10% aqueous sodium hydroxide cooled inan ice bath was added 8 ml. of

dimethyl sulfate in acetone. After three hours of stirring an additional15 ml. of 10% sodium hydroxide and 2 ml. of dimethyl sulfate were addedand the mixture stirred three hours longer. The reaction mixture wasacidified, and the product collected and recrystallized from acetic acidto give 3-carboxy-5-amino-2,4,6-triiodo-N-methylglutaranilic acid, palegray crystals, M.P. 2l8220 C. (dec.).

(b) 3-carboxy-5-glutarimido-2,4,6 triiodo-N-methylglutaranilic acid R isHOOC(CH CON(CH Y is CH CH CH was prepared from 3-carboxy-5-amino-2',4',6-triiodo-N-methylglutaranilic acid and glutaric anhydrideaccording to the procedure of Example 1. The free acid was obtained as acolorless solid, M.P. 160161 C. when recrystallized from acetic acid,and the disodium salt form as a beige solid, M.P. 252-255 C.

(c) 3'-glutarimido-2,4,6-triiodo-N-methylglutaranilic acid [A; R isHOOC(CH CON(CH Y is CH CH CH was prepared from 29.65 g. of the disodiumsalt of 3- carboxy-'-glutarimido-2,4,6' triiodo-N-methylglutaranilicacid in 70 ml. of dimethylformamide, 30 minutes at reflux. The free acidproduct was obtained in the form of a mauve powder, M.P. 256257 C.;sodium salt form, mauve powder, M.P. 24l-245 C.

EXAMPLE 24 (a) 3-carboxy-5-(N methylacetamido)2,4,6-triiodo-N-methylglutaranilic acid [D; R is CH CON(CH R is CH R" isH, Y is CHZCHZCHZ] was prepared from 49.0 g. of3-carboxy-5-(N-methylacetamido)-2- 4,6-triiodoglutaranilic acid (Exampleand ml. of dimethyl sulfate in 175 ml. of 10% sodium hydroxide accordingto the procedure of Example 23. The product was recrystallized fromacetic acid, using ethyl acetate to bring the compound out of solution.There was thus obtained 3-carboxy-5-(N-methylacetamido)-2',5,6triiodo-N-methylglutaranilic acid, colorless prisms, M.P. 284-287 C.(dec.)

(b) 2,4',6-triiodo-3-(N-methylacetamido)-N-methylglutaranilic acid [B; Ris CH CON(CH R is CH R is H, Y is CH CH CH was prepared from 16.42 g. ofthe disodium salt of3'-carboxy-5-(N-methylacetamido)-2,4',6-triiodo-N-methylglutaranilicacid in 40 ml. of dimethylformamide, 30 minutes at reflux. The free acidproduct was recrystallized from aqueous acetic acid and obtained as palecream-colored crystals, M.P. 90l00 C.; sodium salt form, M.P. 173-175 C.

EXAMPLE 25 (a) 3-carboxy-S-(N methylacetamido)-2,4,6triiodo-N-ethylglutaranilic acid [D; R is CH CON(CH R is C H R is H, Yis CH CH CH was prepared from 56.3 g. of3-carboxy-5-(N-methylacetamido)-2, 4,6-triiodoglutaranilic acid (Example10) and 40 ml. of diethyl sulfate in 10% sodium hydroxide solutionaccording to the procedure of Example 23. The product was recrystallizedfrom acetic acid and from an acetic acidethyl acetate mixture to give3-carboxy-5-(N-methylacetamido)-2',4,6'-triiodo-N-ethylglutaranilicacid, M.P. 259 261 C. (dec.).

(b) 2,4',6-triiodo-3-(N methylacetamido)-N-ethylglutaranilic acid [B; Ris CH CON(CH R is C H R is H, Y is CH CH CH was prepared from 44.1 g. ofthe disodium salt of3-carboxy-5-(N-methylacetamido)-2,4,6-triiodo-N-ethylglutaranilic acidin 107 ml. of dimethyl formamide, 45 minutes at reflux. The product hadthe M.P. 112-112.5 C. when recrystallized from aqueous acetic acid3-carboxy-5 (N-methylacetamido) 2',4,6'-triiodoglutaranilic acid cansimilarly be alkylated with n-butyl iodide or 2-hydroxyethyl bromide togive 3-carboxy-5'- (N-methylacetamido)-2,4,6 triiodo-N-butylglutaranilicacid [D; R is CH CON(CH R is C4H9, R is H, Y

is CH CH CH or 3-carboxy-5-(N-methylacetamido)-2,4,6-triiodo-N-(2-hydroxyethyl)glutaranilic acid [D; R is CH CON(CH Ris HOCH CH R is H, Y is CH CH CH which in turn can be decarboxylated togive, respectively,2,4,6-triiodo-3-(N-methylacetamido)-N-butylglutaranilic acid [B; R is CHCON(CH R is C H R is H, Y is CH CH CH or 2,4,6-triiodo-3-(N-methylacetamido) N-(2 hydroxyethyl)glutaranilic acid [B; R is CHCON(CH R is HOCH CH R is H, Y is CH CH CH EXAMPLE 26 (a)3-carboxy-2,4',6' triiodo-5-(Nmethylacetamido)-3,3,N-trimethylglutaranilic acid [D; R is CH3CON(CH3)EXAMPLE 27 N,N-(2,4,6-triiodo-m phenylene)bis(N methylglutaramic acid)[B; R is HOOCCH C-H CH CON(CH R is CH R is H, Y: is CH CH CH disodiumsalt form, colorless prisms, M.P. 241245 C., by methylation ofN,N-(2,4,6-triiodo-m phenylene)diglutaramic acid (Example 14(b).

EXAMPLE 28 2,4,6'-triiodo-3-(N-methylacetamido) N methylsuccinanilicacid [B; R is CH CON (CH R is CH R is H, Y is CH CHz], M.P. 199-200 C.from aqueous acetic acid; sodium salt form, M.P. -l90 C. frommethanol-ether, by methylation of 2,4,6-triiodo-3-(-N-triiodo-3-(N-methylacetamido)succinanilic acid (Example 11(b).

EXAMPLE 29 2,4,6-triiodo-3- (N methylacetamido)-3,N-dimethylglutaraninicacid [B; R is CH CON(CH3), R is CH R is H, Y is CH CH(CH -)CH colorlesspowder,

M.P. 101-1075 C., by methylation of 2',4',6'-triiodo 3'-(Nmethylacetamido) 3 methylglutaraninic acid (Example 13(b)). EXAMPLE 30{N-methyl-N-[2,4,6-triiodo 3 (N-methylacetamido)phenyl]carbamoylmethylthio}acetic acid [B; is

CH CON(CH R is CH R is H, Yis CH SCH tan solid, M.P. 124-129 C.,prepared by hydrolysis of 4-[2,4,6-triiodo- 3-(Nmethylacetamido)phenyl]-3,5 thiamorpholinedione and methylation of theresulting {N-[2,4,6-triiodo- 3 (Nmethylacetamido)phenyl]carbamoylmethylthio} acetic acid. 1

EXAMPLE 31 2,4',6-triiodo-3-(N methylacetamido)-N-methyldiglycolaninicacid [B; R is CH C-ON(CH R is CH R is H, Y is CH OCH colorless solid,M.P. 141- 143" C., prepared by hydrolysis of'N-[2,4,6-triiodo-3-(N-methylacetamido)phenyl]diglycolimide, and methylation of the resulting2',4,6'-triiodo-3-(N-methylacetarnido) diglycolanilic acid.

- 17 EXAMPLE 32 (a) N,N-(2,4,6 triiodo-u,m-toluylene)bis[acetamide] [K;R is CH CQNHCH Q is COCH was prepared by decarboxylation of3-acetamido-5-acetamidomethyl-2,4,6- triiodobenz oic acid according tothe method of Example 1(b), and was obtained in the form of a colorlesssolid, M.P. 28Z-288 C. when recrystallized from acetic acid.

, (b) N,-[2,4,6-triiodo 3 (acetylaminomethyl)phenyl] glutarimid e' [A; Ris CH CONHCH Y is CH CH CH was v prepared by interactinga-acetamido-Z'A,6'-triiodom-acetotoluidide with glutaric anhydrideaccording to the method of Example 2(a), and was obtained in the form ofa colorless solid, M.P. 128-134 C. when recrystallized from isopropylalcohol.

EXAMPLE 33 (a) N-[2,4,6 triiodo 3(acetylaminomethyl)-5-carboxyphenyl1glutarimide [C; R is CH CONHCH Y isOH CH CH was prepared by interacting 3-acetamido-5-acetamidomethyl-2,4,6-triiodobenzoic acid with glutaric anhydrideaccording to the method of Example 2(a), and was obtained in the form ofa colorless solid, M.P. 256- 258 C. when recrystallized from aceticacid.

(b) N-[2,4,6 triiodo-3-(acetylaminomethyl) 5 carboxyphenyl] glutaramicacid [D; R is CH CONHCH R and R" are H, Y is CH CH CH was prepared byhydroylsis ofN-[2,4,6-triiodo-3-(acetylaminomethyl)-5-carboxyphenyl]glutarimide withdilute sodium hydroxide, and was obtained in the form of a colorlesssolid, M.P. 234-239" C. when recrystallized from acetic acid.

(c) N-[2,4,6-triiodo 3 (acetylaminomethyl)phenyl] glutaramic acid [B; Ris CH CONHCH R and R are H, Y' is CH CH CH was prepared bydecarboxylation of N-[2,4,6-triiodo 3(acetylaminomethyl)-5-carboxyphenyl1glutaramic acid according to themethod of Example 1(b), and was obtained in the form of a colorlesssolid, M.P. 2S4259 C. when recrystallized from aqueousdimethylformamide. The same substance can be prepared by hydrolysis ofN-[2,4,6-triiodo-3-(acetylaminomethy1)phenyl]glutarimide (Example 32b)with warm dilute sodium hydroxide.

EXAMPLE 34 N-[2,4,6 triiodo 3 (acetylaminomethyl)phenyl]-N-methylglutaramic acid [B; R is CH CONHCH R is CH R is H, Y is CH CH CHwas prepared by interacting N-[2,4,6-triiodo 3(acetylaminomethyl)phenyl] glutaramic acid (Example 33c) with dimethylsulfate according to the procedure of Example 23, and was obtained inthe form of a colorless solid, M.P. 167175 C. when recrystallized fromethyl acetate.

EXAMPLE 35 (a) Methyl 3-carboxy-2,4,6-triiodo-5-(Nmethylacetamido)azelanilate [D; R is CH CON(CH R is H, R is CH Y is--(CH ,].A mixture of 100 g. of azelaic acid monomethyl ester and 500ml. of thionyl chloride was refluxed for one hour. The excess thionylchloride was removed by distillation and the last traces removed byadding benzene and evaporating the solvent. A solution of 260 g. of3-amino-5-acetamido-2,4,6-triiodobenzoic acid in 3500 ml. of dioxane wasthen added to the resulting acid chloride of azelaic acid monomethylester, and the mixture wasrefluxed for six hours. The dioxane was thenremoved by distillation and the residual product recrystallized fromacetic acid to give methyl 3-carboxy- 2',4,6-triiodo 5'(N-methylacetamido)azelanilate, as colorless needles, M.P. 198203 C.

By replacing the azelaic acid monomethyl ester by a molor equivalentamount of oxalic acid monomethyl ester or malonic acid monomethyl ester,there can be obtained, respectively, methyl 3-carboxy-2',4,6-triiodo 5'(N- methylacetamido)oxalanilate [D; R is CH CON(CH R is H, R is CH Y issingle bond], or methyl 3-carboxy-2,4',6'-triiodo 5(N-methylacetamido)malonani- 18 late [D; R is CH CON(CH R is H, R is CHY is CH (b) 3-carboxy-2,4,6-triiodo 5' (N-methylacetamido)azelanilicacid [D; R is CH CON(CH R and R" are H, Y is -(CH2)q-].--A mixture of136.5 g. of methyl 3'-carboxy-2,4,6-triiodo 5(N-methylacetamido)azelanilate and 180 ml. of water was treated with 10%aqueous sodium hydroxide (about ml.), added dropwise until solution wascomplete. The mixture was heated on a steam bath for ten minutes, 18 ml.more of 10% sodium hydroxide was added, and the mixture heated one hourlonger. The reaction mixture was cooled, acidified with 3% hydrochloricacid, and the solid product collected, washed with water, dried andrecrystallized from acetic acid to give3'--carboxy-2,4,6-triiodo-5'-(N-methylacetamido)azelanilic acid as acolorless solid, M.P. 205- 208 C.

By replacing the methyl 3'-carboxy-2',4',6-triiodo-5'-(N-methylacetamido)azelanilate by a molar equivalent amount of methyl3'-carboxy-2',4,6-triiodo-5-(N-methylacetamido)oxalanilate or methyl3-carboxy-2',4,6'-triiodo-5-(N-methylacetamido)malonanilate there can beobtained, respectively, 3-carboxy-2',4,6-triiodo 5 (N-methylacetamido)oxalanilic acid [D; R is CHgCON (CH R and R are H, Y issingle bond] or 3-carboxy-2,4,6-triiodo-5-(N-methylacetamido)malonanilic acid [D; R is CH CON(CH R and Rare H, Y' is CH (c) 2,4,6-triiodo 3 (N-methylacetamido)azelanilic acid[B; R is CH CON(CH R and R are H, Y is (CH3)7] was prepared bydecarboxylation of 3-carboxy-2',4',6-triiodo 5(N-methylacetamido)azelanilic acid according to the method of Example1(b), and was obtained in the form of a colorless solid, M.P. 153- C.

By replacing the3-carboxy-2,4',6-triiodo-5'-(N-methylacetamido)azelanilic acid by amolar equivalent amount of 3-carboxy-2,4,6-triiodo 5'(N-methylacetamido) oxalanilic acid and 3-carboxy-2,4,6-triiodo 5' (N-methylacetamido)malonanilic acid there can be obtained, respectively,2,4,6-triiodo-3 (N-methylacetamido oxalanilic acid [B; R is CH CONH(CH Rand R are H, Y is single bond] or2,4,6-triiodo-3-(N-methy1acetamido)malonanilic acid [B; R is CH CONH(CHR and R are H, Y is CH Alternatively, 2',4, 6-triiodo-3'-( Nmethylacetamido) azelanilic acid can be prepared by interacting 3-amino-2,4,6-triiodo-N-methylacetanilide [K; R is CH CON (CH Q is H] with theacid chloride or azelaic acid monomethyl ester, and subjecting to mildalkaline hydrolysis the resulting methyl 2,4',6-triiodo 5(N-methylacetamido) azelanilate [B; R is CH CON(CH R is H, R" is CH Y iS(d) 2,4,6-triiodo N methyl-3-(N-methylacetamido)azelanilic acid [B; R isCH CON(CH R is CH R is H, Y is -CH was prepared by methylation of2',4,6-triiodo-3-(N-methylacetamido)azelanilic acid with dimethylsulfate according to the procedure of Example 23, and was obtained inthe form of its sodium salt. colorless solid, M.P. above 125 C.

EXAMPLE 36 (a) N methyl N,N (2,4,6-triiodo-m-phenylene) bis[acetamide][K; R is CH CON(CH Q is COCH was prepared by decarboxylation of3-acetamido-5-(N- methylacetamido)-2,4,6-triiodobenzoic acid accordingto the procedure of Example 1(b), and was obtained in the form of acolorless solid, M.P. 160 C.

(b) 3 maleimido 2,4,6 triiodo-N-methylacetanilide [A; R is CH CON(CH Yis CH=CH-] can be prepared by interacting2,4,6-triiodo-N-methyl-m-benzenediacetamide with maleic anhydrideaccording to the procedure of Example 2(a), or by decarboxylation of2,4,6-

19 triiodo 3 maleimido 5 (N-methylacetamido)benzoic acid, M.P. 312 C.(dec.).

(c) 5' (N methylacetamido) 2,4',6' triiodorna1eanilic acid [B; R is CHCON(CH R and R are H, Y is CH=CH-] can be prepared by hydrolysis of 3-maleimido-Z,4,6-triiodo-N-methylacetanilide with dilute sodiumhydroxide.

I claim:

1. A compound of the formula I wherein Y is an alkylene group of fromtwo to six carbon atoms wherein 2 or 3 carbon atoms separate thecarbonyl groups.

2. N,N' (2,4,6 triiodo-m-phenylene)diglutarimide, according to claim 1wherein Y is CH CH CH References Cited UNITED STATES PATENTS Sauers260-326.5 Wallingford 260326.5 Ackerman .5 260-518 A Ozaki 260-326.5

Straw 260-326 Archer et a1 260-518 Carsen 260-471 Wallingford 260-326.5

Keberlie 260-281 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-239.3 R, 243 B, 247.2, 302 R, 307 B, 326.5 FM, 518 A, 544 Y, 562 R,562 S; 424-5 rat-mt NO. 5 66x408, (SN s u eom- Dated May 2, 19 2Invcntoflff) Jamea H. Acker'man It is certified that error appears inthe above-identifid patent and that said Letters Patent are herebycorrected as shot-:1 below:

601mm '1, formulas {A} and (B) should read P-CO-YCO0R" Signed" andsealed 3rd day of July 1973.

(SE AL) Attest: v

EDWARD M.PLETCI IERJR. Rene Tegtmeyer Attesting Officer A g CommissionerofPatents

